Therapeutic Approaches for NOP Receptor Antagonists in Neurobehavioral Disorders: Clinical Studies in Major Depressive Disorder and Alcohol Use Disorder with BTRX-246040 (LY2940094)

Abstract

Conventional antidepressants increase the efflux of biogenic amine neurotransmitters (the monoamine hypothesis of depression) in the central nervous system (CNS) and are the principle drugs used to treat major depressive disorder (MDD). However, the lack of efficacy in some patients, the slow onset of action, and the side effect profiles of existing antidepressants necessitate the exploration of additional treatment options. The discovery of the nociceptin/orphanin FQ peptide NOP receptor (N/OFQ-NOP receptor) system and its characterization in preclinical biological and pharmacological stress-related conditions supports the potential antidepressant and anti-stress properties of a NOP receptor antagonist for the treatment of neurobehavioral disorders. BTRX-246040 (formerly LY2940094) was designed to test this hypothesis in the clinic. A small clinical proof of concept study demonstrated efficacy of BTRX-246040 in MDD patients. In this study, BTRX-246040 (40 mg, p.o.) significantly reduced negative bias as assessed by the facial recognition test within 1 week of treatment and decreased depression symptoms after 8 weeks. BTRX-246040 also reduced depression symptoms in a second trial with heavy alcohol drinkers. Given the comorbidity of MDD and alcohol use disorder, a compound with such effects in patients could be a valuable addition to the medications available. A proof of concept study showed efficacy of BTRX-246040 in reducing heavy drinking and increasing the probability of abstinence in individuals diagnosed with alcohol dependence. In addition, plasma levels of gamma-glutamyl transferase were decreased by BTRX-246040 compared to placebo control implying improvement in liver function. Collectively, the clinical data reviewed within this chapter suggest that BTRX-264040 functions to normalize dysfunction in reward circuits. The overall efficacy and safety of this compound with a novel mechanism of action are encouraging of further clinical development. BTRX-246040 is currently under development for MDD by BlackThorn Therapeutics.

Notes

Acknowledgments

We thank the book editors for the invitation to review the data on BTRX-246040. JMW also thanks former colleagues with whom he had the pleasure and honor to work with in characterizing LY2940094 (now BTRX-246040). Specifically, he thanks Michael Statnick, Miguel Toledo, Linda Rorick-Kehn, Xia Li, Scott Gleason, Keith Wafford, and Vanessa Barth from Eli Lilly and Company (Indianapolis, Indiana, the USA, and Windlesham, Surrey, the UK), Roberto Ciccocioppo (University of Camerino, Italy), and John Pintar (Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey, USA).

JMW dedicates this review to the memory of creative and energetic chemist, devoted humanitarian, and friend Conception Pedregal, who led the chemistry effort to discover BTRX-246040.

Conflict of Interest

WJM and TLW are employees of and shareholders in BlackThorn Therapeutics which is actively evaluating BTRX-246040 for the treatment of neurobehavioral disorders.

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